Glia cells are an abundant but underappreciated cell type in the central nervous system. As their name implies, glia were long regarded as the glue holding the neurons together, only present to provide structure and nutrients to their more important neuronal neighbors. However, evidence regarding the importance of glia cells to synaptic transmission is quickly emerging. Glia express classical neurotransmitters, exhibit excitability via calcium waves, are integration centers for inputs to the neurons and are regulators of ions, metabolites and neurotransmitters in the synaptic cleft. Glia have also been shown to be an integral part in glutamate recycling. Interestingly, glia are hormonally responsive in their morphology and cellular mechanisms. We have investigated a functional significance for the changes in glial morphology by examining the effect of hormones on the glutamate-glutamine cycle. It is well understood that glial cells play an essential role in the recycling of glutamate in the brain. There are only two enzymes in the glutamate- glutamine cycle: neuronal glutaminase, and glial glutamine synthetase (GS). Our preliminary data demonstrates that in the arcuate nucleus of the adult female rat there is a significant increase in the protein expression of both these enzymes in the presence of estradiol. This brings to the forefront the importance of hormonally responsive glial cells and their role in modulating synaptic transmission. The goal of this proposal will be to examine the role of hormonally responsive astrocytes in glutamate production. Since numerous studies implicate GS as being responsible for a significant portion of glutamate production, we hypothesize that estradiol is acting at the level of the astrocyte to increase GS expression and as a result of the increase in glutamine levels, glutaminase expression is subsequently increased. This proposal seeks to explore the primary site of this novel action of estradiol and further elucidate the role of hormonally responsive astrocytes in this process. These studies will impact research on neurological disorders, which are associated with cerebral glutamate dysfunction [4] and have a hormonal component such as Alzheimer's disease, Parkinson's disease and ALS. Many neurological disorders have two fundamental things in common;first, they affect males and females differently and second, they are caused by abnormal signaling in the brain. In this proposal we will look at estrogens affect normal brain functioning in order to help us pinpoint what goes wrong in an abnormal brain.